Mussel adhesive proteins (MAPs) are remarkable underwater adhesive materials secreted by certain marine organisms which form tenacious bonds to the substrates upon which they reside. During the process of attachment to a substrate, MAPs are secreted as adhesive fluid precursors that undergo a crosslinking or hardening reaction which leads to the formation of a solid adhesive plaque. One of the unique features of MAPs is the presence of L-3-4-dihydroxyphenylalanine (DOPA), an unusual amino acid which is believed to be responsible for adhesion to substrates through several mechanisms that are not yet fully understood. The observation that mussels adhere to a variety of surfaces in nature (metal, metal oxide, polymer) led to a hypothesis that DOPA-containing peptides can be employed as the key components of synthetic medical adhesives or coatings.
Rapid and effective wound closure remains an important goal of modern minimal invasive and conventional surgical procedures. Degradable tissue adhesives offer some advantages over traditional wound closure methods in simplifying complex surgical procedures and eliminating the need for the removal of the device (Sierra & Saltz, Surgical Adhesives and Sealants: Current Technology and Applications. 1996, Lancaster, Pa.: Technomic Publishing Company, Inc., Ikada, Y., Tissue adhesives, in Wound Closure Biomaterials and Devices, C. C. Chu, J. A. von Fraunhofer, and H. P. Greisler, Editors. 1997, CRC Press, Inc.: Boca Raton, Fla. p. 317-346, herein incorporated by reference in their entireties). Few adhesives exist which provide both robust adhesion in a wet environment and suitable mechanical properties to be used as a tissue adhesive or sealant. For example, fibrin-based tissue sealants (e.g. Tisseel VH, Baxter Healthcare) provide a good mechanical match for natural tissue, but possess poor tissue-adhesion characteristics. Conversely, cyanoacrylate adhesives (e.g. Dermabond, ETHICON, Inc.) produce strong adhesive bonds with surfaces, but tend to be stiff and brittle in regard to mechanical properties and tend to release formaldehyde as they degrade.
The FDA has recently approved several types of commercial tissue adhesives for certain uses in the U.S. For example, DermaBond® (Ethicon, Inc.), a cyanoacrylate adhesive, was approved for topical application for closure of skin incisions and lacerations. Although these adhesives cure rapidly and bond strongly to various tissue types, due to toxic degradation products (Refojo et al. Surv. Ophthamol., 1971. 15(4): p. 217-36, herein incorporated by reference in its entirety) this and other cyanoacrylates are not approved for general subcutaneous applications. Tisseel® (Baxter International, Inc.), a fibrin sealant manufactured from pooled blood sources, was approved for use as a hemostatic agent in surgery. While fibrin sealants have excellent hemostatic properties, they do not possess adequate adhesive strengths for proper approximation of wound edges. Furthermore, the use of human-derived components are a potential source of viral transmission (i.e. HIV, hepatitis) (Saltz et al. Plast. Reconstr. Surg., 1991. 88(6): p. 1005-15, herein incorporated by reference in its entirety) and bovine-derived components have been found to lengthen curing time (Banninger et al. J. Haematol., 1993. 85(3): p. 528-32, herein incorporated by reference in its entirety). Gelatin-based adhesives such as gelatin-resorcinol-formaldehyde (GRF) glues have been used clinically in Europe. However, the use of formaldehyde is a major concern these adhesives have yet to be approved by FDA for clinical use in the US. Other tissue adhesives products in the market in some regions include collagen based (e.g. FloSeal), PEG based (e.g. CoSeal), or bovine serum albumin (Bioglue). All of these products suffer low adhesive strength. Although several other types of adhesives and sealants are currently under development, none of the currently available adhesives have proven ideal. Therefore, the need for new adhesive biomaterials with improved properties continues to exist.
There are several prior arts that describe the use of a tissue adhesive in conjunction with a surgical prosthesis for the repair of soft tissue. Oiwa et. al. reported the use of GRF glue with a collagen sheet as a sutureless device for cardiovascular anastomosis (Oiwa et al. Artif Organs, 2001 25(4): p. 281-91, herein incorporated by reference in its entirety). Although wound closure was successful in a canine model, using formaldehyde as the cross-linking reagent is not desirable due to toxicity concerns, and GRF adhesives have not been approved by the FDA for clinical use in the US. Additionally, curing the GRF glue requires mixing the ingredients, which could complicate preparation and intra-operative workflow.
The use of fibrin sealant to secure a non-absorbable synthetic mesh in hernia repair has been reported (Olivier ten Hallers et al. Journal of Biomedical Materials Research Part A, 2006: p. 372-380, Schwab et al. Hernia, 2006. 10: p. 272-277, Topart et al. Surg. Endosc., 2005. 19: p. 724-727, herein incorporated by reference in its entirety). While some level of success was demonstrated, it was noted that fibrin sealant could not adequately prevent mesh migration in some occasions, which is likely due to the weak adhesive strength of the sealant. Additionally, the use of fibrin sealant requires mixing of its ingredients, which could complicate preparation and intra-operative workflow. The use of a cyanoacrylate adhesive has been reported in mesh fixation (Fortelny et al. Surgical Endoscopy, 2007. 21(10): p. 1781-1785, herein incorporated by reference in its entirety). While cyanoacrylate adhesives have significantly higher adhesive strength than fibrin-based adhesives, investigators observed inhibition of tissue integration of the implant material combined with pronounced inflammatory response. Additionally, cyanoacrylate adhesive significantly reduced the elasticity of the mesh and abdominal wall, and impaired the biomechanical performance of the repair. Due to the release of toxic degradation products (formaldehyde), cyanoacrylates are not approved for general subcutaneous applications in the US. Thus, there continues to be a need for an improved and effective fixation device that not only secures the mesh to the abdominal wall, but also enhances the long-term biocompatibility of the repair.
Recently, a film-based tissue sealant, TissuePatch™ and TissuePatchDural™ (TissueMed, Ltd.), received CE mark for lung and dural sealing, respectively. These products are composed of a polymeric film containing N-hydroxysuccinimide (NHS) activated esters that are capable of crosslinking formation with amine groups on soft tissue surfaces.
Based on the limitations of the adhesives in the field, a need exists for materials that overcome current disadvantages.